PROJECT SUMMARY Atrial fibrillation (AF) is a common cardiac arrhythmia and an established risk factor for stroke, heart failure, and dementia. AF prevalence increases exponentially with age, affecting >1 in 10 individuals 70 years of age and older. The burden of AF-related complications is also higher among the elderly, with 1 in 5 strokes among persons 80-89 years of age being attributable to AF. Given current trends in population aging and increased awareness and detection of AF, the number of elderly individuals affected by AF will rise steeply. Though the importance of AF as a comorbidity in the elderly (defined here as individuals ?75 years old) is growing, the evidence base supporting AF management among this group is startlingly sparse. Despite the established value of oral anticoagulation for the prevention of stroke and systemic thromboembolism in AF, these medications are underutilized among the elderly, partly due to an uncertain risk-benefit ratio in the presence of multiple chronic conditions and use of other medications. Similarly, knowledge about the effectiveness of rhythm control strategies, such as antiarrhythmic drugs or catheter ablation, is limited among older AF patients. Thus, the high prevalence of polypharmacy and multimorbidity are two issues making the management of elderly patients with AF particularly challenging, and are extremely likely to influence the effectiveness and risks of established AF treatments. To address this knowledge gap, we propose the following two aims in this R21 application: (1) to evaluate the association of polypharmacy with outcomes (stroke, severe bleeding, heart failure, all-cause hospitalization) and the impact of polypharmacy on the effectiveness (stroke prevention) and risks (severe bleeding) of oral anticoagulants and rhythm control therapies in elderly patients with AF; and (2) to evaluate the association of multimorbidity with the same outcomes as in Aim 1 and the interaction of multimorbidity with oral anticoagulation and rhythm control therapies in the risk of stroke and severe bleeding. We will pursue these aims using data from MarketScan, a large administrative healthcare database that includes clinical information on >500,000 patients with AF ?75 years of age in the period 2007-16. The large sample size, the availability of extensive information on prescriptions and comorbidities, and the application of state-of-the-art approaches for comparative effectiveness research provide a unique opportunity to explore the impact that polypharmacy and multimorbidity have in the management of a large understudied group of AF patients. Findings from this study will inform the development of specific guidelines for the management of elderly patients with AF. Also, we will obtain solid evidence supporting the effectiveness of established treatments of AF in this patient population, which will alleviate concerns regarding risk-benefit trade-offs. Further, we will identify subsets of patients at particular risk of developing treatment complications and provide data that can help patients and clinicians make informed decisions about different treatment approaches.